Macrocyclic LRRK2 kinase inhibitors

Abstract

The present invention relates to novel macrocyclic compounds of formula (I) and compositions containing said compounds acting as kinase inhibitors, in particular as inhibitors of LRRK2 (Leucine-Rich Repeat Kinase 2). Moreover, the present invention provides processes for the preparation of the disclosed compounds, as well as methods of using them, for instance as a medicine or diagnostic agent, in particular for the treatment and/or diagnosis of diseases characterized by LRRK2 kinase activity such as neurological disorders including Parkinson's disease and Alzheimer's disease.

The invention claimed is: 
     
       1. A compound of Formula I or a stereoisomer, tautomer, racemic, salt, hydrate, N-oxide form, or solvate thereof, 
       
         
           
           
               
               
           
         
         Wherein: 
         R 1  is selected from —H, -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 9 R 10 , —(C═O)—R 4 , —(C═S)—R 4 , —SO 2 —R 4 , —CN, —NR 9 —SO 2 —R 4 , —C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, —Ar 1  and -Het 1 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 35 , —NR 11 R 12 , —O—C 1-6 alkyl, and —S—C 1-6 alkyl; 
         R 5  is attached to Z 1  or Z 5  and is selected from —H, -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 6 R 7 , —(C═O)—R 8 , —(C═S)—R 8 , —SO 2 —R 8 , —CN, —NR 6 —SO 2 —R 8 , —C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, —Ar 5  and -Het 5 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 36 , —NR 23 R 24 , —O—C 1-6 alkyl, and —S—C 1-6 alkyl; 
         R 2  is selected from —H, -halo, —OH, —C 1-6 alkyl, and —C 3-6 cycloalkyl; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 27 , and —NR 13 R 14 ; 
         R 3  is selected from —H, -halo, —OH, —C 1-6 alkyl, and —C 3-6 cycloalkyl; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 28 , and —NR 15 R 16 ; 
         R 4  and R 8  are each independently selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 17 R 18 , —C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, —Ar 4  and -Het 4 ; 
         R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 31 , R 32 , R 33 , R 34 , R 35  and R 36  are each independently selected from —H, -halo, ═O, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, —Ar 6  and -Het 6 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, -Het 6 , —Ar 6  and —NR 37 R 38 ; 
         R 27  and R 28  are each independently selected from —H, —C 1-6 alkyl, —C 3-6 cycloalkyl and -Het 2 : 
         R 37  and R 38  are each independently selected from —H, -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, —Ar 7  and -Het 7 ; 
         X 1  is selected from —C 1-6 alkyl-, —O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —C 1-6 alkyl-, —NR 3 -C 1-6 alkyl-, —NR 3 —C 1-6 alkyl-, —NR 3 —, and —O—; wherein each of said —C 1-6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, -phenyl, and —NR 33 R 34 ; 
         X 2  is selected from —C 1-6 alkyl-, —O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —C 1-6 alkyl-NR 2 —C 1-6 alkyl-, —NR 2 —C 1-6 alkyl-, —NR 2 —, and —O—; wherein each of said —C 1-6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, -phenyl and —NR 31 R 32 ; 
         Ar 1 , Ar 4 , Ar 5 , Ar 6 , and Ar 7  are each independently a 5- to 10-membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S; each of said Ar 1 , Ar 4 , Ar 5 , Ar 6 , and Ar 7  being optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and —NR 19 R 20 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; 
         Het 1 , Het 2 , Het 4 , Het 5 , Het 6 , and Het 7  are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S; wherein each of said Het 1 , Het 2 , Het 4 , Het 5 , Het 6 , and Het 7  is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, ═O, —(C═O)—C 1-6 alkyl, and —NR 21 R 22 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; 
         Het 8  is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S;
 wherein said Het 8  is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —C 1-6 alkylene, —C 1-6 alkyl-C 3-6 cycloalkyl, —C 3-6 cycloalkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, ═O, —(C═O)—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl and —NR 21 R 22 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; 
 wherein when R 1  is —H, then at least one heteroatom of Het 8  is attached to X 2 ; 
 
         Z 1 , Z 2 , Z 3 , Z 4  and Z 5  are each independently selected from C and N; and 
         A 1  and A 2  are each independently selected from C and N. 
       
     
     
       2. A compound as defined in  claim 1 , wherein:
 R 1  is selected from —H, -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 9 R 10 , —(C═O)—R 4 , —(C═S)—R 4 , —SO 2 —R 4 , —CN, —NR 9 —SO 2 —R 4 , —C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, —Ar 1  and -Het 1 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 35 , —NR 11 R 12 , —O—C 1-6 alkyl, and —S—C 1-6 alkyl; 
 R 5  is attached to Z 1  or Z 5  and is selected from —H, -halo, —OH, —C 1-6 alkyl, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 6 R 7 , —(C═O)—R 8 , —(C═S)—R 8 , —SO 2 —R 8 , —CN, —NR 6 —SO 2 —R 8 , —C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, —Ar 5  and -Het 5 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 36 , —NR 23 R 24 , —O—C 1-6 alkyl, and —S—C 1-6 alkyl; 
 R 2  is selected from —H, -halo, —OH, —C 1-6 alkyl, and —C 3-6 cycloalkyl; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 27 , and —NR 13 R 14 ; 
 R 3  is selected from —H, -halo, —OH, —C 1-6 alkyl, and —C 3-6 cycloalkyl; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 28 , and —NR 15 R 16 ; 
 R 4  and R 8  are each independently selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 17 R 18 , —C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, —Ar 4  and -Het 4 ; 
 R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 31 , R 32 , R 33  R 34 , R 35  and R 36  are each independently selected from —H, -halo, ═O, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, —Ar 6  and -Het 6 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, -Het 6 , —Ar 6  and —NR 37 R 38 ; 
 R 27  and R 28 , are each independently selected from —H, —C 1-6 alkyl, —C 3-6 cycloalkyl and -Het 2 ; 
 R 37  and R 38 , are each independently selected from —H, -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, —Ar 7  and -Het 7 ; 
 X 1  is selected from —C 1-6 alkyl-, —O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —C 1-6 alkyl-NR 3 —C 1-6 alkyl-, —NR 3 —C 1-6 alkyl-, —NR 3 —and —O—; 
 X 2  is selected from —C 1-6 alkyl-, —O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —C 1-6 alkyl-NR 2 —C 1-6 alkyl-, —NR 2 —C 1-6  alkyl-, —NR 2 —, and —O—; 
 Ar 1 , Ar 4 , Ar 5 , Ar 6 , and Ar 7  are each independently a 5- to 10-membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S; each of said Ar 1 , Ar 4 , Ar 5 , Ar 6 , and Ar 7  being optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and —NR 19 R 20 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; 
 Het 1 , Het 2 , Het 4 , Het 5 , Het 6 , and Het 7  are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S; wherein each of said Het 1 , Het 2 , Het 4 , Het 5 , Het 6 , and Het 7  is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, ═O, —(C═O)—C 1-6 alkyl, and —NR 21 R 22 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; 
 Het 8  is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S;
 wherein said Het 8  is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —C 1-6 alkylene, —C 1-6 alkyl-C 3-6 cycloalkyl, —C 3-6 cycloalkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, ═O, —(C═O)—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl and —NR 21 R 22 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; 
 wherein when R 1  is —H then at least one heteroatom of Het 8  is attached to X 2    
 
 Z 1 , Z 2 , Z 3 , Z 4  and Z 5  are each independently selected from C and N; and 
 A 1  and A 2  are each independently selected from C and N. 
 
     
     
       3. A compound as defined in  claim 1 , wherein:
 R 1  is selected from —H, -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 9 R 10 , —(C═O)—R 4 , —(C═S)—R 4 , —SO 2 —R 4 , —CN, —NR 9 —SO 2 —R 4 , —C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, —Ar 1  and -Het 1 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 35 , —NR 11 R 12 , —O—C 1-6 alkyl, and —S—C 1-6 alkyl; 
 R 5  is attached to Z 1  or Z 5  and is selected from —H, -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 6 R 7 , —(C═O)—R 8 , —(C═S)—R 8 , —SO 2 —R 8 , —CN, —NR 6 —SO 2 —R 8 , —C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, —Ar 5  and -Het 5 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 36 , —NR 23 R 24 , —O—C 1-6 alkyl, and —S—C 1-6 alkyl; 
 R 2  is selected from —H, -halo, —OH, —C 1-6 alkyl, and —C 3-6 cycloalkyl; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 27 , and —NR 13 R 14 ; 
 R 3  is selected from —H, -halo, —OH, —C 1-6 alkyl, and —C 3-6 cycloalkyl; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 28 , and —NR 15 R 16 ; 
 R 4  and R 8  are each independently selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 17 R 18 , —O—C 3-6 cycloalkyl, —C 3-6 cycloalkyl, —Ar 4  and -Het 4 ; 
 R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 31 , R 32 , R 33 , R 34  R 35  and R 36  are each independently selected from —H, -halo, ═O, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, —Ar 6  and -Het 6 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, -Het 6 , —Ar 6  and —NR 37 R 38 ; 
 R 27  and R 28 , are each independently selected from —H, —C 1-6 alkyl, —C 3-6 cycloalkyl and -Het 2 : 
 R 37  and R 38 , are each independently selected from —H, -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, —Ar 7  and -Het 7 ; 
 X 1  is selected from —C 1-6 alkyl-, —O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —C 1-6 alkyl-NR 3 —C 1-6 alkyl-, —NR 3 —C 1-6 alkyl-, —NR 3 —, and —O—; wherein each of said —C 1-6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, -phenyl, and —NR 33 R 34 ; 
 X 2  is selected from —C 1-6 alkyl-, —O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —C 1-6 alkyl-NR 2 —C 1-6 alkyl-, —NR 2 —C 1-6 alkyl-, —NR 2 —, and —O—; wherein each of said —C 1-6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, -phenyl and —NR 31 R 32 ; 
 Ar 1 , Ar 4 , Ar 5 , Ar 6 , and Ar 7  are each independently a 5- to 10-membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S; each of said Ar 1 , Ar 4 , Ar 5 , Ar 6 , and Ar 7  being optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and —NR 19 R 20 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; 
 Het 1 , Het 2 , Het 4 , Het 5 , Het 6 , and Het 7  are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S; wherein each of said Het 1 , Het 2 , Het 4 , Het 5 , Het 6 , and Het 7  is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, ═O, —(C═O)—C 1-6 alkyl, and —NR 21 R 22 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; 
 Het 8  is a bivalent 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S;
 wherein at least one of said heteroatoms is attached to X 1  or X 2 ; 
 wherein when R 1  is —H then at least one heteroatom of Het 8  is attached to X 2 ; and 
 wherein said Het 8  is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —C 1-6 alkylene, —C 1-6 alkyl-C 3-6 cycloalkyl, —C 3-6 cycloalkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, ═O, —(C═O)—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl and —NR 21 R 22 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; 
 
 Z 1 , Z 2 , Z 3 , Z 4  and Z 5  are each independently selected from C and N; and 
 A 1  and A 2  are each independently selected from C and N. 
 
     
     
       4. A compound of Formula Ia or a stereoisomer, tautomer, racemic, salt, hydrate, N-oxide form, or solvate thereof, 
       
         
           
           
               
               
           
         
         Wherein: 
         R 1  is selected from —H, -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 9 R 10 , —(C═O)—R 4 , —(C═S)—R 4 , —SO 2 —R 4 , —CN, —NR 9 —SO 2 —R 4 , —C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, —Ar 1  and -Het 1 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 35 , —NR 11 R 12 , —O—C 1-6 alkyl, and —S—C 1-6 alkyl; 
         R 5  is attached to Z 1  or Z 5  and is selected from —H, -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 6 R 7 , —(C═O)—R 8 , —(C═S)—R 8 , —SO 2 —R 8 , —CN, —NR 6 —SO 2 —R 8 , —C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, —Ar 5  and -Het 5 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 36 , —NR 23 R 24 , —O—C 1-6 alkyl, and —S—C 1-6 alkyl; 
         R 2  is selected from —H, -halo, —OH, —C 1-6 alkyl, and —C 3-6 cycloalkyl; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 27 , and —NR 13 R 14 ; 
         R 3  is selected from —H, -halo, —OH, —C 1-6 alkyl, and —C 3-6 cycloalkyl; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 28 , and —NR 15 R 16 ; 
         R 4  and R 8  are each independently selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 17 R 18 , —C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, —Ar 4  and -Het 4 ; 
         R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 31 , R 32 , R 33  R 34 , R 35  and R 36  are each independently selected from —H, -halo, ═O, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, —Ar 6  and -Het 6 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, -Het 6 , —Ar 6  and —NR 37 R 38 ; 
         R 27  and R 28 , are each independently selected from —H, —C 1-6 alkyl, —C 3-6 cycloalkyl and -Het 2 : 
         R 37  and R 38 , are each independently selected from —H, -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, —Ar 7  and -Het 7 ; 
         X 1  is selected from —C 1-6 alkyl-, —O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —C 1-6 alkyl-NR 3 —C 1-6 alkyl-, —NR 3 —C 1-6 alkyl-, —NR—, and —O—; wherein each of said —C 1-6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, -phenyl, and —NR 33 R 34 ; 
         X 2  is selected from —C 1-6 alkyl-, —O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —C 1-6 alkyl-NR 3 —C 1-6 alkyl-, —NR 2 —C 1-6 alkyl-, —NR 2 —, and —O—; wherein each of said —C 1-6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, -phenyl and —NR 31 R 32 ; 
         Ar 1 , Ar 4 , Ar 5 , Ar 6 , and Ar 7  are each independently a 5- to 10-membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S; each of said Ar 1 , Ar 4 , Ar 5 , Ar 6 , and Ar 7  being optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and —NR 19 R 20 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; 
         Het 1 , Het 2 , Het 4 , Het 5 , Het 6 , and Het  7  are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S; wherein each of said Het 1 , Het 2 , Het 4 , Het 5 , Het 6 , and Het  7  is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, ═O, —(C═O)—C 1-6 alkyl, and —NR 21 R 22 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; 
         Het 8  is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S;
 wherein said Het 8  is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —C 1-6 alkylene, —C 1-6 alkyl-C 3-6 cycloalkyl, —C 3-6 cycloalkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, ═O, —(C═O)—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl and —NR 21 R 22 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; 
 wherein when R 1  is —H then at least one heteroatom of Het 8  is attached to X 2 ; and 
 
         Z 1 , Z 2 , Z 3 , Z 4  and Z 5  are each independently selected from C and N. 
       
     
     
       5. A compound as defined in  claim 4 , wherein:
 R 1  is selected from —H, -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 9 R 10 , —(C═O)—R 4 , —(C═S)—R 4 , —SO 2 —R 4 , —CN, —NR 9 —SO 2 —R 4 , —C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, —Ar 1  and -Het 1 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 35 , —NR 11 R 12 , —O—C 1-6 alkyl, and —S—C 1-6 alkyl; 
 R 5  is attached to Z 1  or Z 5  and is selected from —H, -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 6 R 7 , —(C═O)—R 8 , —(C═S)—R 8 , —SO 2 —R 8 , —CN, —NR 6 —SO 2 —R 8 , —C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, —Ar 5  and -Het 5 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 36 , —NR 23 R 24 , —O—C 1-6 alkyl, and —S—C 1-6 alkyl; 
 R 2  is selected from —H, -halo, —OH, —C 1-6 alkyl, and —C 3-6 cycloalkyl; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 27 , and —NR 13 R 14 ; 
 R 3  is selected from —H, -halo, —OH, —C 1-6 alkyl, —C 3-6 cycloalkyl; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 28 , and —NR 15 R 16 ; 
 R 4  and R 8  are each independently selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 17 R 18 , —C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, —Ar 4  and -Het 4 ; 
 R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 31 , R 32 , R 33 , R 34 , R 35  and R 36  are each independently selected from —H, -halo, ═O, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, —Ar 6  and -Het 6 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, -Het 6 , —Ar 6  and —NR 37 R 38 ; 
 R 27  and R 28 , are each independently selected from —H, —C 1-6 alkyl, —C 3-6 cycloalkyl and -Het 2 : 
 R 37  and R 38 , are each independently selected from —H, -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, —Ar 7  and -Het 7 ; 
 X 1  is selected from —C 1-6 alkyl-, —O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —C 1-6 alkyl-NR 3 —C 1-6 alkyl-, —NR 3 —C 1-6 alkyl-, —NR 3 —and —O—; 
 X 2  is selected from —C 1-6 alkyl-, —O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —C 1-6 alkyl-NR 2 —C 1-6 alkyl-, —NR 2 —C 1-6  alkyl-, —NR 2 —, and —O—; 
 Ar 1 , Ar 4 , Ar 5 , Ar 6 , and Ar 7  are each independently a 5- to 10-membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S; each of said Ar 1 , Ar 4 , Ar 5 , Ar 6 , and Ar 7  being optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and —NR 19 R 20 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; 
 Het 1 , Het 2 , Het 4 , Het 5 , Het 6 , and Het 7  are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S; wherein each of said Het 1 , Het 2 , Het 4 , Het 5 , Het 6 , and Het 7  is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, ═O, —(C═O)—C 1-6 alkyl, and —NR 21 R 22 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; 
 Het 8  is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S;
 wherein said Het 8  is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —C 1-6 alkylene, —C 1-6 alkyl-C 3-6 cycloalkyl, —C 3-6 cycloalkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, ═O, —(C═O)—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl and —NR 21 R 22 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; 
 wherein when R 1  is —H then at least one heteroatom of Het 8  is attached to X 2 ; and 
 
 Z 1 , Z 2 , Z 3 , Z 4  and Z 5  are each independently selected from C and N. 
 
     
     
       6. A compound as defined in  claim 4  wherein:
 R 1  is selected from —H, -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 9 R 10 , —(C═O)—R 4 , —(C═S)—R 4 , —SO 2 —R 4 , —CN, —NR 9 —SO 2 —R 4 , —C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, —Ar 1  and -Het 1 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 35 , —NR 11 R 12 , —O—C 1-6 alkyl, and —S—C 1-6 alkyl; 
 R 5  is attached to Z 1  or Z 5  and is selected from —H, -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NR 6 R 7 , —(C═O)—R 8 , —(C═S)-R 8 , —SO 2 —R 8 , —CN, —NR 6 —SO 2 —R 8 , —C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, —Ar 5  and -Het 5 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 36 , —NR 23 R 24 , —O—C 1-6 alkyl, and —S—C 1-6 alkyl; 
 R 2  is selected from —H, -halo, —OH, —C 1-6 alkyl, and —C 3-6 cycloalkyl; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 27 , and —NR 13 R 14 ; 
 R 3  is selected from —H, -halo, —OH, —C 1-6 alkyl, and —C 3-6 cycloalkyl; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OR 28 , and —NR 15 R 16 ; 
 R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 19 , R 20 , R 21 , R 22 , R 31 , R 32 , R 33  and R 34  are each independently selected from —H, -halo, ═O, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, —Ar 6  and -Het 6 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, -Het 6 , —Ar 6  and —NR 37 R 38 ; 
 R 27  and R 28 , are each independently selected from —H, —C 1-6 alkyl, —C 3-6 cycloalkyl and -Het 2 : 
 R 37  and R 38 , are each independently selected from —H, -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —C 3-6 cycloalkyl, —Ar 7  and -Het 7 ; 
 X 1  is selected from —C 1-6 alkyl-, —O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —C 1-6 alkyl-NR 3 —C 1-6 alkyl-, —NR 3 —C 1-6 alkyl-, —NR 3 —, and —O—; wherein each of said —C 1-6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, -phenyl, and —NR 33 R 34 ; 
 X 2  is selected from —C 1-6 alkyl-, —O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —C 1-6 alkyl-NR 3 —C 1-6 alkyl-, —NR 2 —C 1-6 alkyl-, —NR 2 —, and —O—; wherein each of said —C 1-6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, -phenyl and —NR 31 R 32 ; 
 Ar 1 , Ar 4 , Ar 5 , Ar 6 , and Ar 7  are each independently a 5- to 10-membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and S; each of said Ar 1 , Ar 4 , Ar 5 , Ar 6 , and Ar 7  being optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and —NR 19 R 20 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; 
 Het 1 , Het 2 , Het 4 , Het 5 , Het 6 , and Het 7  are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S; wherein each of said Het 1 , Het 2 , Het 4 , Het 5 , Het 6 , and Het 7  is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, ═O, —(C═O)—C 1-6 alkyl, and —NR 21 R 22 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; 
 Het 8  is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S; wherein at least one of said heteroatoms is attached to X 1  or X 2 ;
 wherein when R 1  is —H, then at least one heteroatom of Het 8  is attached to X 2 ; and 
 wherein said Het 8  is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —C 1-6 alkylene, —C 1-6 alkyl-C 3-6 cycloalkyl, —C 3-6 cycloalkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, ═O, —(C═O)—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl and —NR 21 R 22 ; wherein each of said —C 1-6 alkyl is optionally and independently substituted with from 1 to 3 -halo; and 
 
 Z 1 , Z 2 , Z 3 , Z 4  and Z 5  are each independently selected from C and N. 
 
     
     
       7. A compound of Formula I or a stereoisomer, tautomer, racemic, salt, hydrate, N-oxide form, or solvate thereof as defined in  claim 1 , wherein each of said Z 1 , Z 2 , Z 3 , Z 4  and Z 5  is C. 
     
     
       8. A compound as defined in  claim 1  wherein:
 A 1 and A 2  are each independently selected from C and N; 
 R 1  is selected from —H and -halo; 
 R 5  is selected from —H, -halo and —C 1-6 alkyl; 
 R 2  is selected from —H and —C 1-6 alkyl; 
 R 3  is selected from —H and —C 1-6 alkyl; 
 X 1  is selected from —O—C 1-6 alkyl-, —NR 3 —C 1-6 alkyl-, —NR 3 —, and —O—; 
 X 2  is selected from —C 1-6 alkyl-, —O—C 1-6 alkyl-, —NR 2 —C 1-6 alkyl-, —NR 2 —, and —O—; 
 Het 8  is a 3- to 10-membered heterocycle; wherein said Het 8  is optionally substituted with 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —C 1-6 alkylene, —C 3-6 cycloalkyl, —C 1-6 alkyl-C 3-6 cycloalkyl, —(C═O)—C 1-6 alkyl, and —(C═O)—C 3-6 cycloalkyl; and 
 Z 1 , Z 2 , Z 3 , Z 4  and Z 5  are each C. 
 
     
     
       9. A compound as defined in  claim 8  wherein:
 A 1  and A 2  are each independently selected from C and N; 
 R 1  is selected from —H and -halo; 
 R 5  is selected from —H, -halo and —C 1-6 alkyl; 
 R 2  is selected from —H and —C 1-6 alkyl; 
 R 3  is selected from —H and —C 1-6 alkyl; 
 X 1  is selected from —O—C 1-6 alkyl-, —NR 3 —C 1-6 alkyl-, —NR 3 —, and —O—; 
 X 2  is selected from —O—C 1-6 alkyl-, —NR 2 —C 1-6 alkyl-, —NR 2 —, and —O—; 
 Het 8  is a 3- to 10-membered heterocycle; wherein said Het 8  is optionally substituted with 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —C 1-6 alkylene, —C 3-6 cycloalkyl, and —C 1-6 alkylC 3-6 cycloalkyl; and 
 Z 1 , Z 2 , Z 3 , Z 4  and Z 5  are each C. 
 
     
     
       10. A compound as defined in  claim 8  wherein A 1  is N and A 2  is C. 
     
     
       11. A compound of Formula Ia or a stereoisomer, tautomer, racemic, salt, hydrate, N-oxide form, or solvate thereof, 
       
         
           
           
               
               
           
         
         Wherein: 
         R 1  is selected from —H and -halo; 
         R 5  is attached to Z 1  and is selected from —H and —C 1-6 alkyl; 
         R 2  is selected from —H and —C 1-6 alkyl; 
         R 3  is selected from —H and —C 1-6 alkyl; 
         X 1  is selected from—O—C 1-6 alkyl-, —NR 3 —C 1-6 alkyl-, —NR 3 —, and —O—; 
         X 2  is selected from—O—C 1-6 alkyl-, —NR 2 —C 1-6 alkyl-, —NR 2 —, and —O—; 
         Het 8  is a 3- to 10-membered N-containing heterocycle; wherein said Het 8  is optionally substituted with 1 to 3 substituents selected from -halo, —OH, —C 1-6 alkyl, —C 1-6 alkylene, —C 3-6 cycloalkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, ═O, —(C═O)—C 1-6 alkyl, —C 1-6 alkyl—O—C 1-6 alkyl and —NR 21 R 22 ; and 
         Z 1 , Z 2 , Z 3 , Z 4  and Z 5  are each C. 
       
     
     
       12. A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       13. A compound as defined in  claim 11  which is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       14. A compound as defined in  claim 13  which is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       15. A compound as defined in  claim 12  which is selected from: 
       
         
           
           
               
               
           
         
       
     
     
       16. A compound according to  claim 1 ; wherein R 5  is linked to the aryl or heteroaryl moiety at position Z 1  in accordance with the numbering as provided in Formula I. 
     
     
       17. A compound according to  claim 1 ; wherein said compound is the S-enantiomer. 
     
     
       18. A compound according to  claim 1 ; wherein said compound is the R-enantiomer. 
     
     
       19. A pharmaceutical composition comprising a compound according to  claim 1  and at least one pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
       20. A method for the treatment of a leucine-rich repeat kinase 2 (LRRK2)-kinase associated disease; said method comprising administering to a subject in need thereof an effective amount of a compound according to  claim 1 , wherein the LRRK2-kinase associated disease is a neurological disorder chosen from Parkinson's disease and Alzheimer's disease. 
     
     
       21. A method for inhibiting the activity of a leucine-rich repeat kinase 2 (LRRK2), the method comprising administering to a subject in need thereof an effective amount of a compound according to  claim 1 . 
     
     
       22. A compound of Formula Ia or a stereoisomer, tautomer, racemic, salt, hydrate, N-oxide form, or solvate thereof as defined in  claim 6 , wherein each of said Z 1 , Z 2 , Z 3 , Z 4  and Z 5  is C.